The proposed studies will assess the role of alpha6beta4 integrin-induced VEGF expression in mammary tumorigenesis. Specifically, we will examine the hypothesis that alpha6beta4 mediates mammary tumor formation and progression by allowing for sustained VEGF expression in breast cancer cells, in vivo, leading to increased survival of breast cancer cells through autocrine VEGF signaling. A key role for alpha6beta4 in regulating VEGF expression and carcinoma progression, in vitro, is suggested by many past studies, but it is essential that these findings be confirmed, in vivo. Using orthotopically transplanted breast cancer cells with expression of beta4 integrin reduced by an inducible siRNA, along with a transgenic knockout approach, the role alpha6beta4 in mammary tumor formation and progression will first be investigated, in vivo. Next, the effect of reduced beta4 integrin expression on sustained VEGF expression in breast carcinomas, in vivo, will be assessed. Also, the ability to recover tumor formation and progression, which is expected to be reduced in beta4-deficient breast tumors, by adding back VEGF will be examined. Finally, the effect of reduced beta4-induced VEGF expression on tumor angiogenesis will be determined. [unreadable] [unreadable] [unreadable] [unreadable]